ITTO970268A1 - INSECTICIDE ASSOCIATION AGAINST THE FLEAS OF MAMMALS, IN PARTICULAR OF DOGS AND CATS. - Google Patents

Description

The present invention refers to an improvement of the procedures for combating fleas of mammals, and in particular of dogs and cats. It also refers to a new composition for this use, on the basis of a combination which associates in a way synergistic some parasiticides already known. Finally, it refers to the use of such parasiticides already known for the preparation of this composition.

A new range of insecticides based on 1-N-arylpyrazoles has been described in patents EP-A-295.217 and EP-A-352.944. The compounds belonging to the groups defined in these patents are extremely active and one of these compounds is 1- [2,6-Cl2 4-CF3 phenyl] 3-CN 4- [S0-CF3] 5-NH2 pyrazole, whose name is fipronil , has proved particularly effective not only against crop parasites, but also against mammalian ectoparasites and in particular, but not exclusively, against fleas, ticks, flies and myiasis.

Some compounds with an ovicidal and / or larvicidal effect intended for the immature stages of various ectoparasites are already known, for example from patent US-A-5.439.924. Among these compounds JIGR) are some compounds regulating the growth of insects which act by blocking the development of immature stages (eggs and larvae) towards the adult stage, or by slowing down the synthesis of chitin.

Furthermore, patent FR-A-2.713.889 is known which generally describes the association of at least one compound of the IGR type (insect growth regulator), comprising compounds with juvenile hormone activity and synthesis inhibitors. of chitin, with at least one of the three-compounds N-arildiazole, in particular the fight against various insects to different species.

The compositions can be used in very different forms, without specifying either which applications they are intended for, for example veterinary, sanitary or phytosanitary, or which parasites they are respectively assigned to.

The only application that can be assumed to belong to the veterinary field is associated with the example of manufacturing a pesticide collar, with a slow dispensing formula.

The invention aims to improve the procedures for combating fleas found in small mammals, and in particular in dogs and cats.

The invention has in particular the objective of using parasiticides already known to prepare a composition which is very active against the fleas of these animals.

Finally, the invention has the objective of a new composition thus prepared and intended in particular for the fight against fleas.

By flea in the appropriate sense of the present invention, we mean all the species of traditional or accidental parasitic fleas belonging to the siphohatteri family, and in particular the Ctenocephalid species, especially felis and canis, the rat fleas (Xenopsylla cheopis) and humans (Pulex irritans).

The high efficacy of the process and composition according to the invention implies not only a great instantaneous efficacy, but also a very long-lasting efficacy-after the treatment of the animal.

The invention relates to a procedure for the fight against fleas of small mammals, and in particular of dogs and cats, for a long time, characterized by the fact that the animal undergoes the treatment by local skin application, preferably localized on a reduced area (in English "spot-on"), with effectively parasiticidal doses and proportions, by at least one compound (A) belonging to formula (I):

(the)

or ImethylU ^ or a halogen atom /

- R2 is / S, (0) nR3 o. 4 ^ 5-dicyanoimidazole 2-yl or haloalkyl; ''

- R3 is alkyl or haloalkyl;

R4, represents a hydrogen or halogen atom; or a radical -NR5R6, S (0) mR7, C (0) 0Ri, alkyl, haloalkyl or 0R8, or a radical -N = C (R9) (RIO);

- R5 and R6 independently represent the hydrogen atom or an alkyl radical, haloalkyl, C (0) alkyl, alkoxylcarbonyl, S (0) c-CF3 / or R3⁄4 and Re can together form a divalent alkylene radical which can be interrupted by one or two divalent heteroatoms, such as oxygen or sulfur;

- R7 represents an alkyl radical o. haloalkyl;

- Ra represents an alkyl, haloalkyl radical or a hydrogen atom;

- R9 represents an alkyl radical or a hydrogen atom;

- Rio represents a phenyl or heteroaryl group, optionally substituted by one or more halogen atoms or by groups such as OH, -O-alkyl, S-alkyl, cyano or alkyl;

- Rn and R12 represent, independently of each other, a hydrogen or halogen atom or possibly CN or N02;

- Ri3 represents a halogen atom or a haloalkyl, haloalkoxyl, S (O) qCF3 or SF5 group;

- m, n, q and r represent, independently from each other, an integer equal to 0, 1 or 2;

- X represents a trivalent nitrogen atom or a C-RI2 radical, the other three valences of the carbon atom belonging to the aromatic cycle;

provided that, when Ra is methyl, R3 is haloalkyl, R4 is NH2, Rn is CF3 and X is N; or that R2 is 4,5-dicianoimidazole 2-yl, R4 is Cl, Rn is Cl, Ru is CF3 and X is = C-C1;

and on the other hand, from at least one compound (B) of the .IGR (growth regulator, insect) type, in a fluid vehicle acceptable to the animal and convenient for local skin application.

Preferably, in the formula (I):

- Ri is CN or methyl;

R2 is S (0) nR3;

- R3 is alkyl or haloalkyl;

- R4 represents a hydrogen or halogen atom; or a radical NR5R6, S (0) mR7, C (0) R7, alkyl, haloalkyl or Re or a radical -N = C (R9) R (I);

- R5 and R6 independently represent the hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, S (O) r-CF3 radical; or R5 and R5 can together form an alkylene radical which can be interrupted by one or two divalent heteroatoms such as oxygen or sulfur;

- R7 represents an alkyl or haloalkyl radical;

- Rg represents an alkyl, haloalkyl radical or a hydrogen atom;

- Rg represents an alkyl radical or a hydrogen atom;

- Rio represents a phenyl or heteroaryl group, optionally substituted by one or more halogen atoms or by groups such as OH, -O-alkyl, S-alkyl, cyano or alkyl;

- Rn and R12 represent, independently of each other, a hydrogen or halogen atom;

- Rn represents a halogen atom or a haloalkyl, haloalkoxyl, S (O) qCF3 or SF5 group;

they represent, independently of one another, an integer equal to 0,

- X represents: a trivalent atom or a C-R12 radical, the other three valences of the carbon atom belonging to the aromatic cycle

provided that, when Ri is methyl, R3 is therefore haloalkyl, R4 is NH2, Ru is Cl, Ri3 is CF3 and X is N.

Above all, the compounds of formula (I) in which Ri is CN will be chosen. Compounds in which R2 is S (0) nR3 / preferably with n = 1, R3 being preferably CF3 O alkyl, for example methyl or ethyl, or n - 0, R3 preferably CF3, will also be chosen, as well as those in which X = C-Ri2, being a halogen atom. Compounds in which Ru is a halogen atom, as well as those in which Ri3 is haloalkyl, preferably CF3, are also preferential. Within the scope of the present invention, compounds grouping two or more of these characteristics will be advantageously selected.

A preferential range of compounds of the formula (I) consists of compounds such that Ri is CN, R3 is haloalkyl, R4 is NH2, Ru and Ri2 are, independently of each other, a halogen atom, and / or R13 is haloalkyl .

In these compounds, R3 preferably represents CF3 O ethyl.

The alkyl radicals of the definition relating to the compounds of the formula (I) generally comprise from 1 to 6 carbon atoms. The cycle formed by the divalent alkylene radical representing R5 and R6, as well as the nitrogen atom to which R5 and R6 are associated, is generally a 5, 6 or 7 ring cycle.

A compound of formula (I) particularly preferential in the invention is 1- [2,6-Cl2 4-CF3 phenyl] 3-CN 4- [SO-CF3] 5-NH2 'pyrazole, whose common name is phipronil .

It is also possible to mention the two compounds which differ from the previous one for the following characteristics: <'>

1 - n = 0, R3 = CF3

2 - n = 1, R3 = ethyl.

Among the compounds (B) we can mention in particular the compounds simulating the juvenile hormones, in particular:

azadirachtin - Agridyne

<"> diòlphenolane (Ciba Geigy)

phenoxy carbons (Ciba Geigy)

idroprene (Sandoz)

chinoprene (Sandoz)

metoprene (Sandoz)

pyriproxylphene (Sunitomo / Mgk)

tetrahydroazadirachitin (Agridyne)

and 4-chloro-2- (2-chloro-2-methylpropyl) -5- (6-iodo-3-pyridimethoxy) pyridizine-3 (2H) -one and chitin synthesis inhibiting agents, in particular:

chlorfluazurone (Ishiara Sangyo)

cyromazine (Ciba Geigy)

diflubenzurone (Solvay Duphar)

fluazurone (Ciba Geigy)

fluocycloxurone (Solvay Duphar)

fluphenoxurone (Cyanamid)

esaflumurone (Dow Elanco)

lufenurone (Ciba Geigy)

tebufenozide (Rohm & Haas)

tef lubenzurone (Cyanamid)

triflumurone (Bayer)

these compounds being defined by their common international name (The Pesticide Manual, 10th edition, 1994, Ed. Clive Tomlin, Great Britain).

<r> Si <"> may also mention, as chitin synthesis inhibiting agents, some compounds such as 1'1- (2,6-difluorobenzoyl) -3- (2-fluoro-4- (trifluoromethyl) phenyl urate, 1 '1- (2,6-difluorobenzoyl) -3- (2-fluoro-4- (1,1,2,2-tetra-fluoroethoxyl) phenylurate, 1'1- (2,6-difluorobenzoyl) - 3- (2-fluoro-4-trifluoromethyl) phenylurate.

Novalurone (Isagro, an Italian company) can also be mentioned as compound (B).

The preferential compounds (B) are ά metoprene, pyriproxyphenes / hydroprene, cyromazine, lufenurone and 1'1- (2,6-difluorobenzoyl) -3- (2-fluoro-4- (trifluoro-methyl) phenylurate .

A further preferential compound (B) is constituted by novalurone (Isagro, an Italian company).

It is preferable that the administration of the two types of compound be concomitant and preferably simultaneous.

It is preferable that the treatment according to the invention is used for both, or, preferably, three months on the dog and three months on the cat.

Preferably, the treatment is carried out in such a way as to administer to the animal a variable dose from 0.1 to 40 and in particular from 1 to 20 mg / kg for derivative (A) and a variable dose from 0.1 to 40> in in particular from 1 to 30 mg / kg for compound (B).

Preferential doses range from 5 to 15 mg / kg for compound (A) and from 0.5 to 15 mg / kg for preferential compounds (B), or from 10 to 20 mg / kg for other compounds (B) .

In another way of using the process according to the invention, the application of compounds (A) and (B) can be distinguished and separated in time. It is therefore preferable to alternate the applications, for example with an interval of one month between two applications, the first application being preferably carried out with compound (A).

It is evident that the dose values thus indicated are average values which can vary widely, due to the fact that a formulation having defined dosages in the compound (A) of the 1-N-phenylpyrazole derivatives and in the compound (B) will be practically administered to animals of relatively different weights. Consequently, the doses actually applied often turn out to be lower or higher by a factor, to reach 2, 3 or 4 with respect to the preferential dose, without causing toxic risks for the animal in the event of overdose, while maintaining a real efficacy that may be lower. duras

The aim of this procedure is not therapeutic and refers in particular to cleaning the hair and skin of animals by eliminating the parasites present, as well as their residues and manure. The treated animals thus have a hair that is more pleasing to the eye and to the touch.

The invention also relates to this procedure for therapeutic purposes, intended to treat and prevent parasites having pathogenic consequences.

In accordance with the present invention, the process described above can also be used to combat ectoparasites, in particular ticks.

The invention also relates to a composition, in particular intended for the fight against fleas found in small mammals, characterized in that it comprises on the one hand at least one compound (A) of formula (I) such as the one defined above, and on the other hand at least one compound (B) above, in doses and proportions having a parasiticidal efficacy for the pùlcè in a carrier fluid acceptable for the animal and with a local skin application, preferably localized on a small area .

Preferably, in the formula (I):

- Ri is' CN or methyl

- R2 is s (.0) „R3

-n is alkyl or haloalkyl

- R4 represents a hydrogen or halogen atom; or a radical NR5R6, S (0) mR7, C (0) R7, alkyl, haloalkyl or 0R8, or a radical -N = C {R9) (R10);

- R5 and R6 independently represent the hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, S (O) r-CF3 radical; or R5 and Rs can together form a divalent alkylene radical which can be interrupted by one or two divalent heteroatoms such as oxygen or sulfur;

- R7 represents an alkyl or haloalkyl radical;

- Re represents an alkyl, haloalkyl radical or a hydrogen atom;

- R9 represents an alkyl radical or a hydrogen atom;

- R \ o represents a phenyl or heteroyl group optionally substituted by one or more halogen atoms or groups such as OH, -O-alkyl, S-alkyl, cyano or alkyl;

- Rii and Ri? they represent, independently of one another, a hydrogen or halogen atom;

- Rj3 represents a halogen atom or a haloalkyl, haloalkoxyl, S (O) qCF3 or SF5 group;

- m, n, q and r represent, independently from each other, an integer equal to 0, 1 O 2;

- X represents a trivalent nitrogen atom or a C-RI2 radical, the other three valences of the carbon atom belonging to the aromatic cycle; provided that, when Ri is methyl, R3 is haloalkyl, R4 is NH2, Rn is Cl, RI3 is CF3 and X is N.

Above all, the compounds of formula (I) in which Ri is CN will be chosen. Compounds in which R2 is S (0) nR3, preferably with n = 1, R3 preferably being CF3 O alkyl, for example methyl or ethyl, or n = 0, R3 preferably CF3, will also be chosen, as well as those in which X = C-RI2, being a halogen atom. The compounds in which R <"> u is a halogen atom, as well as those in which R3 is haloalkyl, preferably CF3, are also preferential.

A preferential range of compounds of formula (I) consists of compounds such that Rj is CN, R3 is haloalkyl, R4 is NH2, Rn and RI2 are, independently of each other, a halogen atom, and / or R13 is haloalkyl .

In these compounds, R3 preferably represents CF3 or ethyl.

A compound of formula (I) particularly preferable in the invention is 1- [2,6-Cl2 4-CF3 phenyl] 3-CN 4- [SO-CF3] 5-NH2 pyrazole.

It is also possible to mention the two compounds which differ from the previous A for the following characteristics:

The preparation of the compounds of formula (I) can be carried out in accordance with one of the processes described in patent applications WO-A-87/3781, 93/6089 and 94/21606 or in European application EP-A-0.295.117, or any other relevant procedure within the competence of the specialist in the chemical synthesis sector. For the chemical realization of the products of the invention, it is believed that the skilled in the art has at his disposal, among other things, all the contents of "Chemical Abstracts" and of the documents cited therein.

Among the IGR-type compounds listed above, methoprenes, pyriproxylphenes, hydroprene, cyromazine, lufenurone and 1'1- (2,6-difluorobenzoyl) -3- (2-fluoro-4- ( trifluoro-methyl) phenylurate.

Novalurone is also preferential.

The proportions by weight of the compounds of the formula (I) and of the compound (B) are preferably comprised between 80/20 and 20/80.

The fluid carrier can be simple or complex and is adapted to the chosen route and mode of administration.

The compositions for punctual application can advantageously comprise:

b) a crystallization inhibitor agent, in particular present in quantities ranging from 1 to 20% (W / V), preferably from 5 to 15%, this inhibiting agent corresponding to the test according to which:

They are deposited for 24 hours on a glass sheet at 20 ° C 0.3; ml of a solution A consisting of

followed, as well as 10% of this inhibiting agent, after which few or no crystals, in particular less than 10 crystals, preferably 0 crystals, are observed with the naked eye on the glass sheet;

c) an organic solvent having a dielectric constant between 10 and 35, preferably between 20 and 30, the content of this solvent c) in the overall composition preferably representing the 100% complement of the composition; d) an associated organic solvent having a boiling point lower than 1.00 ° C, preferably lower than 80 ° C and having a dielectric constant between 10 and 40, preferably between 20 and 30; this associated solvent can advantageously be present in the composition according to a weight / weight ratio (P / P) of points d) / c) comprised between 1/15 and 1/2. The solvent is volatile in order to act as a drying accelerator and can be mixed with water and / or solvent c).

Although this is not preferential, the composition for point application can optionally comprise water, in particular in an amount ranging from 0 to 30% (volume by volume V / V), in particular from 0 to 5%.

The composition with point application can also comprise an antioxidant agent intended to inhibit oxidation by air, this agent being present in particular in a variable quantity from 0.005 to / 1% (W / V), preferably from 0.01 to 0.05 %.

The compositions according to the invention intended for pets, in particular for dogs and cats, are generally applied by skin application (in English "spot-on" or "pour-on"); it is generally a localized application on a surface area of less than 10 cm <2>, in particular between 5 and 10 cm <2>, above all in particular in two points and preferably located between the shoulders of the animal. After application, the composition spreads over the entire body of the animal, then dries without crystallizing or modifying its appearance (in particular the absence of any whitish or dusty residue), nor the sensation that contact with the hair gives.

The <'> compositions with point application according to the invention are particularly advantageous for their effectiveness, for their rapidity of action, as well as for the pleasant appearance of the fur of the animals after application and drying.

As organic solvent c) usable in the invention, the following can be mentioned in particular: acetone, acetone nitrile, benzyl alcohol, butylglycol, dimethylacetamide, dimethylformamide, n-butyl ether of dipropylene glycol, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, monomethyl ether. of dipropylene glycol, liquid polyoxylethylene glycols, propylene glycol, 2-pyrrolidone, in particular N-methyl pyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, or a mixture of at least two of them.

As crystallization inhibiting agent b) usable in the invention, the following can be mentioned in particular:

- polyvinylpyrrolidone, polyvinyl alcohols, vinyl acetate and vinylpyrrolidone copolymers, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, sorbitan polyoxylethyleate esters; lecithin, sodium carboxylmethylcellulose, acrylic derivatives such as methacrylates and others;

- anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium; calcium stearate; triethanolamine stearate; sodium abietate; alkyl sulphates, in particular sodium lauryl sulfate and sodium ketyl sulfate; sodium dodecylbenzenesulphonate, sodium dioctyl sulfoccinate; fatty acids, in particular those derived from copra oil;

- cationic surfactants such as water-soluble quaternary ammonium salts of the formula N + R'R "R '" R "", Y ", in which the radicals R are hydrocarbonate radicals, possibly hydroxylated, and Y" is an anion of an acid strong such as halide, sulfate and sulfonate anions; ketyltrimethylammonium bromide is one of the cationic surfactants that can be used;

- the amine salts of the formula N + R'R "R '", in which the radicals R are hydrocarbonate radicals, optionally hydroxylated; octadecylamine hydrochloride is one of the cationic surfactants that can be used;

- non-ionic surfactants such as sorbitan esters, optionally polyoxyethylenated, in particular Polysorbate 80, polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, ethylene oxide and propylene oxide copolymers;

- amphoteric surfactants such as lauryl compounds substituted by betaine

or preferably a mixture of at least two of them.

Particularly preferably, a crystallization inhibitory pair will be used, that is the combination of a polymeric type smoke agent and a surfactant. These agents will be selected in particular among the compounds mentioned as crystallization inhibiting agent b).

Among the particularly interesting polymeric film-forming agents, we can mention:

- the various grades of polyvinylpyrrolidone,

- polyvinyl alcohols, e

- copolymers of vinyl acetate and vinylpyrrolidone.

As regards the non-sorbitan polyoxyethylene surfactant surfactants and in particular the different grades of Polysorbate, for example Polysorbate 80.

In particular, the filmogenic agent and the surfactant can be introduced, in similar or identical quantities, within the limit of the total quantities of crystallization inhibiting agent mentioned elsewhere.

The couple thus constituted considerably guarantees the objectives of absence of crystallization on the hair and preservation of the cosmetic appearance of the fur, that is to say without tendency to stick or take on a sticky appearance, despite the high concentration of active substance.

As associated solvent d), the following can be mentioned in particular: absolute ethanol, isopropanol and methanol.

As an antioxidant agent, classical agents are used in particular, such as: butylhydroxylanisole, butylhydroxytoluene, ascorbic acid, sodium metabisulphite, propyl gallate, sodium thiosulfate or a mixture of two of them at the most.

The compositions for point application according to the invention are traditionally prepared by simply mixing constituents such as those previously defined; it is advantageously started by mixing the active substance in the main solvent, and the other ingredients or additives are then added.

The applied volume can vary from about 0.3 to 1 ml, preferably about 0.5 ml for the cat and about 0.3 to 3 ml for the dog, depending on the weight of the animal.

Particularly preferentially, the composition according to the invention can be in the form of a solution, suspension or concentrated emulsion for a punctual application on a small skin area of the animal, generally between the two shoulders (solution of the "spot type" -on "). In a much less preferential way, it is possible to provide forms of solution or suspension to be pulverized, of solution, suspension or emulsion to be poured on the animal ("pour-on" type solution), of oil, of cream, of ointment or any other fluid formulation, for topical administration.

<^> Advantageously, the composition ready for use is dosed in a variable quantity from 0.1 to 40 mg / kg of compound (A) of the formula (I) and variable from 0.1 to 40 mg / kg of compound ( B).

Preferably, a dosed formulation ready for use, in particular for spot-on application, contains from 1 to 20 mg / kg, preferably from 2 to 10 mg / kg of compound (A), in particular the fipronil, and from 1 to 30 mg / kg, preferably from 2 to 10 mg / kg of preferential compound (B) or from 10 to 20 mg / kg of the other compound (B).

It is possible advantageously to provide ready-to-use compositions dosed for animals with a respective weight of 1-10, 10-20, 20-40 kg.

In another embodiment foreseen for a separate application over time, it is possible to realize a composition in the form of a set (kit) grouping, in the same package, a composition containing a compound of the formula (I), in particular the fipronil , and a composition containing compound (B) preferably pyriproxylphene, each of the compositions comprising a vehicle allowing its own skin application.

Preferably, each of the two compositions is provided for a "spot-on" local application and a container is preferably provided containing only the dose necessary for each application.

Thus, a set may contain, for example in a package, three containers, each comprising a single dose of composition of the compound (A) and three containers each containing a single dose of composition of the compound (B), the containers (A) distinguishing from the containers (B) for some markings, shapes or colors, as well as a table specifying that the containers (A) and (B) must be used alternately, for example with an interval of one month, and starting for example from a container (A ).

The compositions according to the invention, in particular those with punctual application, have proved to be extremely effective for the very long-lasting treatment of mammalian fleas, and in particular of small mammals such as dogs and cats.

The discovery that compound (A), such as fipronil, dissolves in the sebum to cover the whole animal and concentrates in the sebaceous glands, from which it is progressively expanded over a long period, constitutes the plausible explanation for this lasting efficacy for these compositions, and could perhaps also explain the lasting action of the associated compound (B).

They also have a certain effectiveness against other parasitic insects and in particular against ticks, and it is evident that it is possible to extend the application of the composition according to the invention to the treatment of ectoparasites, even endoparasites, for which the composition is equipped with .a real utility and likely to be obtained practically according to the criteria of the veterinary sector.

Thus, a composition based on fipronil and fluazurone can also be used, for example, in particular against ticks.

If necessary, the composition according to the invention can also comprise a further insecticide, and in particular the imidacloprid.

The invention also relates to the use of at least one compound (A) of the formula (I) and of at least one compound (B) of the IGR type, such as those defined above, for the preparation of a composition such as that defined above.

Other advantages and characteristics of the invention will appear upon reading the following description, carried out by way of non-descriptive example.

The following example of preparation includes compound (A ') of formula (I) as compound (A).

By way of example, to prepare a composition for local skin application according to the invention, the following components can be advantageously mixed:

al - compound (B) in a variable quantity from 1 to 20% (percentage by weight by volume W / V);

a2 - compound (A) of formula (I), in an amount ranging from 1 to 20%, preferably from 5 to 15% (percentage by weight by volume (PV).

By way of example, the compositions of the invention comprise the subsequent concentrations (P / V) of compounds (A) and (B), in a liquid medium comprising a representative of each of the components b, c and d. The total volume is 1 ml.

Example 1

fipronil 10%

pyriproxylphene 5%.

Example 2

fipronil 5%

pyriproxylphene 5%

L -Example "3

fipronil 5%

pyriproxylphene 20%

Example 4

fipronil 10%

metoprene 30%

Example 5

fipronil 10%

1 - (2,6-difluorobenzoyl) - 3- (2-fluoro-4-trifluoromethyl) phenylurate 5%.

A few cats are infested, with 100 fleas each, then re-infested every 10 days. Simultaneously with the first manifestation, they receive a local cutaneous application, in a variable quantity from 0.1 mg / kg of the composition according to example 1. Two months after the treatment and ten days after the last infestation, no flea is detected and eggs. collected turned out to be non-viable.

Dogs treated with compositions conforming to examples 1 and 2 following the same procedure, the same treatment efficacy two months of the composition.

Claims (2)

CLAIMS 1. Composition for protection a. long, lasting against fleas of small mammals, and in particular of dogs and cats, characterized by the fact that it comprises on the one hand at least one compound (A) of formula (I): in which: - Ri is CN or methyl or a halogen atom; - R2 is S (0) nR3 or 4,5-dicianoimidazole 2-yl or haloalkyl; r-R3 is alkyl or haloalkyl; R4 represents a hydrogen or halogen atom; or a radical -NR5R6, S (0) n, R7, C (0) O-R7, alkyl, haloalkyl or OR0, or a radical -N = C (R9) (RIO); - R5 and R0 independently represent the hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, alkoxylcarbonyl, S (O) r-CF3 radical; or R5 and R6 can together form a divalent alkylene radical which can be interrupted by one or two divalent heteroatoms, such as oxygen or sulfur; - R7 represents an alkyl or -haloalkyl radical; - Re represents an alkyl, haloalkyl radical or a hydrogen atom; - R9 represents an alkyl radical or a hydrogen atom; - Rio represents a phenyl or heteroaryl group, optionally substituted by one or more halogen atoms or by groups such as OH, -O-alkyl, S-alkyl, cyano or alkyl; - Ru and Ri2 represent, independently of each other, a hydrogen or halogen atom or possibly CN or N02; - RI3 <'> represents a halogen atom or a haloalkyl, haloalkoxyl, S (0) qCF3 or SF5 group; - m, n, q and r represent, independently from each other, an integer equal to 0, 1 or 2; - X represents a trivalent nitrogen atom or a C-Ri2 radical, the other three valences of the carbon atom belonging to the aromatic cycle; provided that, when R1 is methyl, R3 is haloalkyl, R4 is NH2, Ru is CF3 and X is N; or that R2 is 4,5-dicianoimidazole 2-yl, R4 is Cl, Ru is Cl, RJ3 is CF3 and X is = C-C1; on the other hand, at least from an IGR-type ovicidal compound (B) regulating the growth of insects, in a fluid vehicle acceptable to the animal and suitable for local skin application. 2. Composition according to claim 1, characterized in that the compound of formula (I) is such that: - Ri is CN or methyl; - R2 is S (0) nR3; - R3 is alkyl or haloalkyl; - .R4 represents a hydrogen or halogen atom; or a radical NR5R6, S (0) raR7, C (0) R7, alkyl, ’haloalkyl or R8 or a radical -.R (I); Rè independently represent the atom: of hydrogen or "an alkyl radical, haloalkyl, C (0) alkyl, S (0) r-CF3; or R5 and R6 can together form an alkylene radical which can be interrupted by one or two heteroatoms divalents such as oxygen or sulfur; “R-? · Represents an alkyl- or haloalkyl radical; - Re represents an alkyl, haloalkyl radical or a hydrogen atom; - Rg represents an alkyl radical or a hydrogen atom; - Rio represents a phenyl or heteroaryl group, optionally substituted by one more halogen atoms or by groups such as OH, -O-alkyl, S-alkyl, cyano or alkyl; - Rn'and 'R12 represent, independently of one another, a hydrogen or halogen atom; - R13 represents a halogen atom or a haloalkyl, haloalkoxyl, 'S (0) qCF3' or SF5 group; '. - m, n, q and r represent, independently; one from the other, an integer equal to 0, 1 or r, ·: · ' X represents a trivalent atom or a C-R12 radical, the other three valences of the carbon atom belonging to the aromatic cycle provided that, when Ri is methyl, R3 is therefore 'haloalkyl, R4 is NH2, Rn is Cl, R13 both CF3 and X is N. 3. Composition according to claim 1, characterized in that the compound of formula (I) is such that Ri is CN. 4. A composition according to one of claims 1 to 3, characterized in that the compound of formula (I) is such that R3 is haloalkyl, preferably CF3. 5. Composition according to one of claims 1 to 4, characterized in that the compound of formula (I) is such that R2 is S (0) nR3, preferably with n = 1, R3 preferably being CF3 or alkyl, in particular methyl or ethyl, or n = 0 ', R3 preferably being CF3. 6. Composition according to one of claims 1 to 5, characterized in that the compound of formula (I) is such that X is C-R12, with R12 representing a halogen atom. according to one of the claims from l to 6, characterized by the fact that "the compound formula (I) is such that Ri is CN, R3 is -haloalkyl, R4 is NH2, Rn and RI2" are, regardless of 'other, .uri'. 'halogen atom, and / or Rl3 is haloalkyl. 8. Composition according to any one of claims 1 to 7, wherein the compound of formula (I) is: 1- [2, .6-Cl24-CF3 phenyl] 3-CN 4- [SO-CF3] 5-NH2 pyrazole. 9. Composition according to any one of claims 1 to 7, wherein the compound of formula (I) is one of the following compounds: 1: 1— [26-Cl2 4-CF3. phenyl] 3-CN .4- [S-CF3] 5-NH2 pyrazole; 2: 1- [2, 6-Cl2 4-CF3 phenyl] 3-CN 4- [SO-C2H5] -NH2 pyrazole. Composition according to any one of claims 1 to 9, characterized in that compound (B) is a juvenile hormone simulating compound, in particular: azadirachtin diofeholano ffenpssildarbo metoprene pyriproxylphenene tetrahydroazadirachitin i '- and 4-chloro-2- (2-chloro-2-methylpropyl;) -5r {6 -lodo - 3 - pyridylmethoxy); pyridizhafir3 (2H) -one or a chitin synthesis inhibitor, in particular: chlorf luazurone cyromazine diflubehzurone fluazurone fluocycloxurone fluphenoxurone esaflumurone lufenurone tebufenozide teflubenzurone triflumurone 1 '1- {2,6-difluorobenzoyl) -3- (2-fluoro-4- (trifluoromethyl) phenyl urate, 1-1- (2,6-difluorobenzoyl) -3- (2-fluoro-4- (1,1 , 2,2-tetrainoro e-. Toxyl) phenylurate, 1'1- (2,6-difluorobenzoyl) 3-; (2-fIuorb-4-trifluoromethyl) phenylurate. conforming to one of the claims characterized by the fact that i 12. Composition according to the claim characterized in that the IGR-type compound is selected among the methoprene, the pyriprosilphenes, the lufenurone and 1 '1- (2,6-difluorobenzoyl) -3- (2-fluoro-4- ( trifluoro-methyl) phenylurate. 13. Composition according to one of claims 1 to 12, characterized in that the proportions by weight of compounds (A) of formula (I) and compounds of type (B) are between 80/20 and 20/80 . Composition according to one of claims 1 to 13, characterized in that the fluid carrier and the concentration of compounds (A) and (B) are adapted to an application by means of a "spot-on" type skin deposit. 15. Composition according to one of claims 1 to 14, characterized in that the fluid carrier and the concentration of compounds (A) and (B) are adapted to an application by punctual skin deposit of the "pour- 16 '. Composition according to any one of claims 1 ': to 15, characterized in that the fluid carrier and the concentration of compounds (A) and (B) are adapted to a localized application on a surface area of less than 10 cm2 , in particular between 5 and 10 cm2, in particular in two points and preferably located between the shoulders of the animal. 17. Composition according to any one of claims 1 to 16, characterized in that it is dosed from 0.1 to 40 mg / kg of compound (A) and from 0.1 to 40 mg / kg of compound (B) . 18. Composition compliant with claim 17, characterized in that it is dosed from 1 to 20 mg / kg, - in particular from 2 to 10 mg / kg of compound (A) and from 1 to 30 mg / kg of compound (B) . 19. Composition according to any one of claims 1 to 18, characterized in that it further comprises a crystallization inhibiting agent (b), in particular present in an amount ranging from 1 to 20% (W / V), preferably from 5 at 15%. 20. Composition according to claim 17, characterized in that the crystallization inhibiting agent (b) is selected from: - polyvinylpyrrolidone, polyvinyl alcohols, vinyl acetate and vinylpyrrolidone copolymers, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxylethylene sorbitan esters; <; > lecithin, sodium carboxylmethylcellulose, acrylic derivatives such as methacrylates and others; - anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium; calcium stearate; triethanolamine stearate; sodium abietate; alkyl sulphates, in particular sodium lauryl sulfate and sodium kethyl sulfate; sodium dodecylbenzenesulphonate, sodium dioctyl sulfoccinate; fatty acids, in particular those derived from copra oil; - cationic surfactants such as the water-soluble quaternary ammonium salts of the formula N <+> R'R "R '" R "", Y <~>, in which the radicals R are hydrocarbonate radicals, possibly hydroxylated, and Y <" > it is an anion of a strong acid such as halide, sulphate and sulfonate anions; ketyltrimethylammonium bromide is one of the cationic surfactants that can be used; - the amine salts of the formula N <+> R'R "R '", in which the radicals R are hydrocarbonate radicals, optionally hydroxylated; octadecylamine hydrochloride is one of the cationic surfactants that can be used; - non-ionic surfactants such as sorbitan esters, optionally polyoxyethylenated, in particular Polysorbate 80, polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylene derivatives of castor oil, polyglycerol esters, polyoxyethylene fatty alcohols, polyoxyethylene fatty acids, ethylene oxide and propylene oxide copolymers; - amphoteric surfactants such as lauryl compounds substituted by betaine or preferably a mixture of at least two of them. 21. Composition according to any one of claims 19 and 20, characterized in that it further comprises a crystallization inhibitory pair formed by the combination of a film-forming agent of the polymeric type and a surfactant, in particular in similar or identical quantities, in the limit of the total quantities of crystallization inhibiting agent. 22. Composition according to claim 21, characterized in that the film-forming agent is selected from: - the various grades of polyvinylpyrrolidone, - polyvinyl alcohols, e - copolymers of vinyl acetate and vinylpyrrolidone; and characterized in that the surfactant is selected from among the non-ionic surfactants, preferably the polyoxyethylenated sorbitan esters, in particular the various grades of Polysorbate. 23. Composition according to any one of claims 1 to 22, characterized in that it comprises an organic solvent (c) having a dielectric constant between 10 and 35, preferably between 20 and 30, the content of which in the overall composition preferably represents the 100% complement of the composition. 24. Composition according to claim 23, characterized in that the organic solvent (c) is selected from acetone, acetone nitrile, benzyl alcohol, butylglycol, dimethylacetamide, dimethylformamide, n-butyl ether of dipropylene glycol, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, monomethyl ether of dipropylene glycol, liquid polyoxylethylene glycols, propylene glycol, 2-pyrrolidone , in particular N-methyl pyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, or a mixture of at least two of them. 25. Composition according to any one of claims 23 and 24, characterized in that it further comprises an associated organic solvent (d) boiling point lower than 100 ° C, preferably lower than 80 ° C and having a dielectric constant between 10 and 40, preferably between .20 and -30 mixable with water and / or solvent c), the latter being present in particular according to a weight / weight ratio (P / P) associated solvent (d) / solvent (c) included between 1/15 and 1/2. 26. Composition according to claim 25, characterized in that the associated solvent (d) is selected from absolute ethanol, isopropanol and methanol. ~ 27j Composition according to any one of claims 1 to 26, characterized in that it is made in the form of a separately grouped unit in the same package of the compound (B), and a table specifying that the containers (A) and (B) they must be used alternately, in particular with an interval of one month. 28. Composition according to any one of claims 1 to 27, characterized in that it provides protection for a duration ranging from 2 to 3 months. 29. Use of a part of at least one compound (A) belonging to formula (I): in which: - Ri is CN or methyl or a halogen atom; - R2 is S (0) nR3 or 4,5-dicyanoimidazole 2-yl or -haloalkyl; <r> - R3 is alkyl or haloalkyl; - R4 represents a hydrogen or halogen atom; or a radical -NR5R6, S (0) mR7, C (0) O-PR ?, alkyl, haloalkyl or 0R8, or a radical -N = C (Rg) (Rio); - R5 and R6 independently represent the hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, alkoxyl carbonyl, S (O) r-CF3 radical; or R5 and R6 can together form a divalent alkylene radical which can be interrupted by one or two divalent heteroatoms, such as oxygen or sulfur; - R7 represents an alkyl or haloalkyl radical; - Ra represents an alkyl, haloalkyl radical or a hydrogen atom; - Rg represents an alkyl radical or a hydrogen atom; - Rio represents a phenyl or heteroaryl group, optionally substituted by one or more halogen atoms or by groups such as OH, -O-alkyl, S-alkyl, cyano or alkyl; - Rn and Ri2 represent, independently of each other, a hydrogen or halogen atom or possibly CN or N02; - R13 represents a halogen atom or a haloalkyl, haloalkoxy, S (O) qCF3 or SF5; - m, n, q and r represent, independently from each other, an integer equal to 0, 1 or 2; - X represents a trivalent nitrogen atom or a C-R12 radical, the other three valences of the carbon atom belonging to the aromatic cycle; provided that, when R1 is methyl, R3 is haloalkyl, R4 is NH2, Ru is CF3 and X is N; or that R2 is 4,5-dicianoimidazole 2-yl, R4 is Cl, Ru is Cl, R13 is CF3 and X is —C — C1 / and on the other hand, at least by an IGR-type ovicidal compound (B) regulating the growth of insects, for the preparation of a composition intended for local skin application, for long-lasting protection against fleas of small mammals, and in particular of dogs and cats. Use according to claim 29 for the preparation of a composition according to any one of claims 1 to 28. 31. Use in accordance with any of claims 1 to 28 to combat ectoparasites, in particular ticks. Process to combat fleas of and in particular of dogs and cats for a long duration / characterized in that the animal is treated by local skin application, in doses and proportions effectively parasiticides, of a composition conforming to any of the claims 1 to 28. 33. Process according to claim 32, characterized in that the animal is treated by means of a point-on-point local skin application of the "spot-on" type. 34. Process according to any one of claims 32 and 33, to combat ectoparasites, in particular ticks.